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Alnylam’s Amyloidosis Drug Holds up in Second Clinical Trial

Alnylam Pharmaceuticals’s (NASDAQ: ALNY) turnaround over the past few years started when a drug for a rare disease called transthyretin (TTR) amyloidosis showed promise in a small clinical trial: its stock traded at $12 per share a year ago, and sits at about $31 per share today.

While the Cambridge, MA-based biotech still has a long way to go to begin selling its first marketed product, it was able prove this weekend that those early results were no fluke.

Alnylam on Sunday revealed interim details from a 25-patient, mid-stage clinical trial of ALN-TTR02, its RNA-interference drug for TTR amyloidosis. The study backs up an early stage trial Alnylam completed in 2012 in that suggested that ALN-TTR02 reduced the level of patients’ TTR, the disease-causing protein that builds up in the tissue of the body as a result of the condition, over one cycle of treatment.

Alnylam reported Sunday that the trend continued in a trial testing patients over two cycles: once either every three weeks or four weeks. It reported that the drug’s effects were statistically significant, meaning they weren’t the result of chance, and that the treatment was generally safe and well-tolerated by patients.

Though Alnylam only reported the safety findings for patients at the highest dose (0.30 mg/kg) over a two-month span, it said there were no significant adverse events so far. One patient on that regimen had a “mild infusion-related reaction” that was curbed as the infusion rate was slowed down. Other side effects seen were fever/chills and polyuria (excessive urination). No patients dropped out of the study, Alnylam said.

Alnylam presented the data at the 2013 Biennial Meeting of the Peripheral Nerve Society in France. It will release the full results of the trial at the International Symposium on Familial Amyloidotic Polyneuropathy in Rio de Janeiro in November.

Further, Alnylam plans to begin an extension study this year of the patients who are in the current trial, and kick-start a pivotal late-stage clinical trial by the end of 2013.

TTR amyloidosis is an inherited condition in which excessive amounts of amyloid proteins build up in tissues of the body, leading to progressive damage to the heart and nerves, and ultimately death. About 10,000 people in the world have the nerve-damaging form of TTR amyloidosis (called familial amyloidotic polyneuropathy, or FAP), while an estimated 40,000 worldwide have the form that affects the heart (named familial amyloidotic cardiomyopathy, or FAC), according to Alnylam.

People who develop symptoms of FAP—typically those between 40 and 60 years old—tend to live for another five to 15 years after their symptoms appear. Those diagnosed with FAC typically live about 2.5 more years, Alnylam says.

The only options for people with the FAP are a liver transplant or Pfizer’s tafamidis (Vyndaqel), which is approved in Europe but rejected by the FDA in July 2012. There are no approved therapies for patients with FAC.

Alnylam, however, is behind Isis Pharmaceuticals (NASDAQ: ISIS) and GlaxoSmithKline (NYSE: GSK), which are co-developing a rival drug for the condition. Isis and GSK started a Phase 2/3 clinical trial for the drug, known as ISIS-TTRrx, in February.

Here’s how Alnylam tested the drug. Alnylam enrolled 25 patients with early stage TTR amyloidosis at 10 sites in Portugal, France, Sweden, Germany, Spain, Brazil, and the U.S. Investigators gave the patients injections of ALN-TTR02 either once every three weeks or four weeks, at dose levels ranging from 0.01 mg/kg to 0.30 mg/kg.

Patients were given a total of two doses, meaning the study period lasted either six weeks or eight weeks, depending on which regimen patients were on. Alnylam’s earlier study tested the safety of one dose of the drug in healthy volunteers.

Alnylam’s goal was to see if the drug was safe and well-tolerated, if higher doses of the drug quickly knocked down more TTR proteins than lower doses, and if its effects lasted through the two-stage regimens.

Alnylam has reported data from the first 19 patients from the study. Those patients were broken into five groups. Four of those groups were administered doses of 0.01 mg/kg (four patients), 0.05 mg/kg (three patients), 0.15 mg/kg (three patients), or 0.30 mg/kg (six patients) of ALN-TTR02 once every four weeks for two months. The other group (three patients) got the strongest dose of the drug once every three weeks.

The 0.15 mg/kg group saw their TTR levels down about 74.5 percent on average four weeks after the first injection, and 77 percent four weeks after the second one. Patients on the two-month, 0.30 mg/kg regimen saw their TTR levels down an average of 82.6 percent after the first month, and 84.8 percent after the second. The most aggressive regimen (0.30 mg/kg once every three weeks) had the best results: an 83.1 percent average drop of TTR levels after three weeks, and an 87.4 percent average after six weeks.

Alnylam also reported that 16 of the 19 patients were already taking drugs that help stabilize TTR levels such as tafamidis, meaning the drug was just as effective in reducing TTR in those patients as it was in patients taking ALN-TTR02 alone.

While the results appear to show that ALN-TTR02 is working, they will have to hold up much longer than just two cycles given the chronic nature of the disease. Furthermore, reduced TTR levels are more of a scientific indicator than an established clinical goal that will catch the eye of regulators in a longer, larger trial.

That’s why Alnylam’s extension study—through which it will test patients on the 0.30 mg/kg dose over two years—will include several clinically validated goals such as a neuropathy impairment score, or “NIS,” for patients, which measures neurological function in their legs. Alnylam will have to hit marks like this if it hopes to really prove that the drug has a positive, tangible effect on patients.

Sanofi’s Genzyme unit holds Asian rights to Alnylam’s broader ALN-TTR program, which includes ALN-TTR02 and a version Alnylam is developing to be injected just under the skin (ALN-TTRsc). Alnylam has the rights to sell the drug, should it make it through clinical trials and win approval from regulators, in the rest of the world.

Tekmira Pharmaceuticals (NASDAQ: TKMR) will get a $5 million payment when ALN-TTR02 enters a pivotal clinical trial, and will get royalties on future sales. Those payments were part of a settlement between the two companies in 2012. Alnylam licenses Tekmira’s RNAi drug delivery technology to help administer ALN-TTR02.

Ben Fidler is Xconomy's Deputy Editor, Biotechnology. You can e-mail him at bfidler@xconomy.com Follow @benthefidler